What we know about nociplastic pain

We expect to feel pain when we stub our toe or touch a hot stove. But pain in the absence of any obvious injury has been a challenge to understand — both for clinicians and patients.

Nociplastic pain refers to a change in pain perception that is not due to tissue damage. The idea that pain can be real — and not just imagined — without tissue damage in the body has long been debated. But researchers and clinicians have begun to see a shift toward acceptance after decades of scholarly work to describe this type of pain and the introduction of the term nociplastic pain in 2016. 

“Nociplastic pain has become more broadly recognized as a third pain mechanism,” said Chelsea Kaplan, PhD, research assistant professor in the University of Michigan Medical School (UMMS) Department of Anesthesiology. “This recognition brings potential de-stigmatization for patients — but it also brings a need for broader understanding: What are the mechanisms of nociplastic pain? What are the risk factors for developing it? How can clinicians recognize it?”  

Kaplan is lead author of the review article, “Deciphering nociplastic pain: clinical features, risk factors and potential mechanisms,” which was commissioned by Nature Reviews Neurology and published last month.

Kaplan and additional review authors from UMMS Daniel Clauw, MD, Steven Harte, PhD, and Andrew Schrepf, PhD, share more about nociplastic pain and what patients and clinicians need to know.

Widespread body pain is the most distinctive symptom, but patients experience other symptoms as well 

Nociplastic pain is altered pain processing despite the lack of clear tissue damage or disease. Instead of something wrong in the periphery that is causing this pain, most of the evidence points to nociplastic pain being driven by changes in the way the central nervous system processes pain. 

“A third mechanistic descriptor was needed to fill the gap between the existing descriptors of nociceptive and neuropathic, acknowledging the complexity of pain experiences that could not be fully described by these previous two categories,” said Steven Harte, PhD, associate director of Michigan Medicine’s Chronic Pain and Fatigue Research Center and senior author of the review article. 

“This new descriptor provides validation for patients with this type of pain and encourages a broader and more nuanced approach to pain assessment and treatment that reflects the latest advances in pain science.”

The hallmark symptom of nociplastic pain is widespread body pain (pain present in multiple regions across the body or the presence of multiple chronic pain conditions). Other common symptoms include: 

• Fatigue
• Poor sleep
• Depressed mood
• Problems concentrating 
• Sensitivity to sensory stimuli (e.g., bright lights, loud sounds).  

Risk factors vary across your lifespan

Nociplastic pain can develop at any point in life, but risk factors vary by age and may also be compounded. Some conditions like irritable bowel syndrome and chronic pelvic pain most commonly develop from post-puberty to middle-age, while a condition like fibromyalgia may be diagnosed later in life.

The biggest risk factors that contribute to development of nociplastic pain include:

• Sex — all nociplastic pain conditions are 1.5-2 times more common in female patients
• Adverse or traumatic childhood experiences
• Puberty (pain increases dramatically during puberty)
• Physical inactivity
• Sleep disturbances

Recognizing the different risk factors and pain conditions across the lifespan could play an important role in early intervention, Kaplan said.

“Clinicians often hear from patients who develop some type of pain during childhood, and then, maybe, dysmenorrhea when they're a teenager, other pain conditions when they're young adults — you see this trajectory and then eventually a diagnosis of fibromyalgia,” she said. 

“If we recognize earlier that all of these pain conditions are nociplastic and are treated differently than other types of pains, that could open up this opportunity to intervene earlier before pain really becomes entrenched and someone is dealing with it for an entire lifetime.”

Research suggests that there may be an underlying neural vulnerability in which brain function predisposes some to developing nociplastic pain.

Brain imaging studies may hold important information about what role the brain plays in nociplastic pain. For example, in a 2022 publication from Kaplan, children underwent brain imaging at the start of the Adolescent Brain Cognitive Development Study; at that time, all of the children were pain free.

One year later, some of the children had developed new onset multi-site pain — pain in multiple body regions, which is one of the key indicators of nociplastic pain. Looking back at the original imaging, a year prior to developing pain, those who had developed pain had increased connectivity between certain brain regions that are associated with pain processing. 

“These brain regions that we found increased connectivity to are some of the regions that come up over and over again when you look in literature of adults with existing nociplastic pain,” Kaplan said.

There are no quick fixes — but a strong patient-clinician partnership can help tailor a treatment plan

Before treatment begins, the review article team say it’s important for clinicians to start with an acknowledgement of the realness of a patient’s pain.

“There are no quick fixes — it’s not like surgery where you can cut something out and make it better,” said Daniel Clauw, MD, director of the Chronic Pain and Fatigue Research Center. 

“But that doesn’t mean the pain isn’t real; it’s just a different mechanism that responds to different treatments. Validating a patient’s experiences and pain will help build the patient-clinician partnership and is an important step in encouraging patients to take an active role in their care.”  

Treatment of nociplastic pain has become much more integrative and is tailored to each patient. A treatment plan may include: 

• Lifestyle changes like getting better sleep, becoming more active and reducing stress
• Psychological therapies like practicing mindfulness or cognitive behavioral therapy (CBT) 
• Non-pharmacological therapies like physical therapy, acupuncture or Tai Chi
• Treatment of comorbidities including depression, anxiety and PTSD
• Pharmacological therapies such as serotonin-noradrenaline reuptake inhibitors 

There’s still a lot we don’t know … 

When asked about next steps for understanding nociplastic pain, the review article team points to two areas of study. 

The authors speak briefly in the paper about two potential subtypes of nociplastic pain that have important treatment applications. Harte first discussed this idea in a 2018 review, but more studies are needed to further define these subtypes. 

Another area of interest is looking at how the immune system and the brain interact and how that contributes to nociplastic pain.

“The key has been getting researchers to embrace the mystery — these symptoms have an enormous effect on people and yet they are poorly understood,” said Andrew Schrepf, PhD, assistant professor of anesthesiology and obstetrics and gynecology.

“The neurobiologists and clinicians who determine how best to treat nociplastic pain are going to have an incredible impact on millions of people.”

… but the recognition of nociplastic pain is an important milestone for patients

Chronic pain experts like Clauw have worked with patients and studied conditions like fibromyalgia for decades. For him, a comprehensive publication within Nature Reviews Neurology serves as both validation for longtime patients and as a starting point for those just beginning their journey.

“For patients who have been told they were making symptoms up, I hope this brings a feeling of credibility,” he said. “And for those who are still looking for answers: Share this with your provider. Share the review article with your provider and ask if they’d be willing to help you work through this. Hopefully, we are giving people — patients, providers, researchers — a playbook for what we know and where to start.”

Additional authors: Eoin Kelleher, Anushka Irani

Disclosures: D.J.C. has consulted for Aptinyx, Daiichi Sankyo, Intec, Lundbeck, Pfizer, Regeneron, Samumed, Teva, Theravance, Tonix, Virios and Zynerba; has received research funding from Aptinyx, Cerephex and Pfizer; and has been involved in litigation testifying against opioid manufacturers in the States of Oklahoma and Florida. S.E.H. has consulted for Aptinyx, Dana- Farber Cancer Institute, Indiana University Indianapolis, Memorial Sloan Kettering Cancer Center, University of North Carolina-Chapel Hill and Wayne State University; has received research funding from Aptinyx and Arbor Medical Innovations, LLC; and holds the following patents: EP2482716B1, US9307906B2, WO2011041683A2, CA2775775C, AU2010300372B2, US11701092B2, USD1010145S1, US20230077464A1 (pending), CN115720508A (pending), CA3177295A1 (pending) and EP4142583A1 (pending). All other authors declare no competing interests.

Paper cited: “Deciphering nociplastic pain: clinical features, risk factors and potential mechanisms,” Nature Reviews Neurology. DOI: 10.1038/s41582-024-00966-8

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